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British Journal of Haematology, 2003, 120, 177–186
THE ROLE OF HYDROXYUREA IN SICKLE CELL DISEASE
Although the molecular basis for the sickling disorders was
ism by which hydroxyurea induces HbF is still unclear.
identified more than 50 years ago (reviewed in Weatherall
Unlike several of the other HbF-inducing agents, such as
2001), progress towards definitive therapy for sickle cell
5-azacytidine and butyrates, hydroxyurea does not appear
disease (SCD) has been frustratingly slow. Until the mid-
to directly modulate globin gene expression by altering
1990s, treatment was almost entirely supportive with no
methylation or binding to transcriptionally active elements.
clinically useful drugs available to prevent or reverse the
That hydroxyurea is a ribonucleotide reductase inhibitor
polymerization of HbS. However, a number of key observa-
and arrests cells in S-phase as a result of impairment of DNA
tions about the role of HbF (Stevens et al, 1981; de Simone
replication is well known. It may therefore increase HbF
et al, 1982, Platt et al, 1984, 1991; Veith et al, 1985;
indirectly by killing rapidly dividing late erythroid cells,
Noguchi et al, 1993) led, in 1995, to the publication of a
causing recruitment of more primitive erythroid precursors
crucially important study in which a new therapeutic agent,
which in turn produce high levels of HbF, or by acting
hydroxyurea, was heralded as a major breakthrough in the
directly on the primitive precursors thereby stimulating HbF
management of SCD (Charache et al, 1995; Schechter &
production (Kolata, 1984). However, even in the early
Rodgers, 1995). The initial clinical trials of hydroxyurea in
trials, it was clear that induction of HbF was unlikely to
SCD were stopped early as a result of outstanding results in
explain all the clinical effects of hydroxyurea; treatment was
the treatment arm and the drug was rapidly licensed in the
often associated with clinical improvement well before any
USA for the treatment of patients with severe SCD. Since
detectable laboratory rise in HbF and the level of HbF did
then, hydroxyurea has been used successfully in a variety of
not always predict response, other variables such as
situations in SCD, including new studies in very young
neutrophil counts and mean cell volume (MCV) often being
children (Wang et al, 2001). However, doubts remain both
more strongly correlated with reduction in symptoms
about its efficacy and safety in the long term.
(Charache et al, 1995).
This review aims to outline current information about the
mechanisms of action of hydroxyurea in SCD, its clinical
Effects of hydroxyurea on red cell–endothelial cell interactions
efficacy in sickling disorders, the approaches to monitoring
An important experimental observation is that within
treatment and to update the evidence about its short-term
2 weeks of commencing hydroxyurea therapy, prior to
and long-term toxicity.
any rise in HbF, sickle erythrocytes show reduced adhesionto endothelial cells under low shear flow conditions (Bridgeset al, 1996). Other investigators have shown that hydroxy-
MECHANISMS OF ACTIONS OF
urea reduces adhesion molecule expression on sickle eryth-
HYDROXYUREA (TABLE I)
rocytes, including very late activation antigen-4 and CD36
The principal rationale for treatment with hydroxyurea is its
(Styles et al, 1997). Erythrocytes from hydroxyurea treated
ability to induce HbF (Letvin et al, 1984). However,
patients also show reduced adhesion in vitro to thrombo-
hydroxyurea appears to exert its beneficial effects in SCD
spondin and laminin (Hillery et al, 2000). As transit times
via a number of additional mechanisms, including modifi-
through hypoxic postcapillary venules are critical in
cation of red cell–endothelial cell interactions and the
promotion of sickling and microvascular occlusion, any
rheological properties of HbS-containing red cells and via its
reduction in sickle–endothelial adhesion would be predicted
myelosuppressive effects, particularly on neutrophils.
to have a beneficial effect.
Effects of hydroxyurea on sickle red cell rheology
The increase in HbF induced by hydroxyurea appears to
Other rheological properties of sickle erythrocytes may also
interfere with HbS polymerization both by preventing
be important, including erythrocyte hydration status and
effective contact between adjacent HbS molecules and also
whole cell deformability, both of which can be increased by
by forming mixed hybrids with HbS that have greater
hydroxyurea (Ballas et al, 1989). An animal model of sickle
solubility than HbS polymers. However, the exact mechan-
cell disease, the transgenic sickle (SAD) mouse, has beenused to investigate these properties further. Hydroxyureacauses increased cellular potassium levels and reducederythrocyte density. Subsequent exposure to chronic hyp-
Correspondence: Professor Irene Roberts, Department of Haema-
oxia led to reduced cellular dehydration compared with
tology, Faculty of Medicine Imperial College, Hammersmith Campus,
untreated animals (de Franceschi et al, 1999). Human
Du Cane Road, London W12 0NN, UK. E-mail: irene.roberts@ic.ac.uk
studies have not always shown consistent results with
2003 Blackwell Publishing Ltd
Table I. Mechanisms of action of hydroxyurea in SCD.
Increase in haemoglobin F
Interferes with HbS polymerization
Reduced red cell–endothelial interactions
Reduced adhesion under low shear flowReduced VLA-4 and CD36 expression on sickle erythrocytesReduced adhesion to thrombospondin and laminin
Improved red cell rheology
Improved erythrocyte hydration statusIncreased whole cell deformabilityReduced red cell density
Reduced neutrophil counts? leads to reduced pro-inflammatory mediators
Nitric oxide release, leading to vaso-dilatation and? reduced platelet activation
respect to cell hydration, although there appears to be an
efficacy. In these studies, using small numbers of patients
alteration in the density profile with a reduction in both
with homozygous SCD, hydroxyurea consistently led to
low-density reticulocytes and high-density sickle cells
increases in the number of erythrocytes and reticulocytes
(Charache et al, 1987; Orringer et al, 1991).
containing HbF (F cells and F reticulocytes respectively), inthe overall percentage of HbF, and in the MCV. Some studies
Myelosuppressive effects of hydroxyurea
also showed an increase in steady-state haemoglobin with
Myelosuppressive effects of hydroxyurea may also be
reductions in neutrophils and reticulocytes, improved red
important in reduction of symptoms. The fall in neutrophil
cell survival and improved red cell filterability (Rodgers et al,
count appears especially important, and neutrophilia has
1993). These encouraging laboratory changes were accom-
long been identified as a marker of severity in SCD (Platt
panied by a lack of evidence of serious toxicity (Charache
et al, 1994). Neutrophils release powerful pro-inflammatory
et al, 1992) and led to the Multicenter Study of Hydroxy-
mediators which are important in endothelial damage and
urea in Sickle Cell Anemia (MSH) study (Charache et al,
cytokine release, both of which trigger sickling (Noguchi
et al, 1993). Neutrophils may also contribute to slow transittime via their adhesive properties and an increase in whole
The Multicenter Study of Hydroxyurea in Sickle Cell Anemia
blood viscosity. Evidence that hydroxyurea may modulate
This study ran from January 1992 until June 1994
neutrophil activation comes from a recent study by
(Charache et al, 1995). The trial was stopped 10 months
Benkerrou et al (2002), who showed that hydroxyurea
early because of a significant reduction in events in the
treatment in patients with SCD corrected the dysregulated
hydroxyurea group. The study was a double-blind, rand-
omized controlled trial of 299 patients with severe SCD
increased hydrogen peroxide production characteristic of
(defined as at least three painful crises per year) recruited
neutrophil activation in SCD.
from 21 centres in the USA and Canada. All patients hadHbSS. Treatment was started at a dose of 15 mg ⁄ kg ⁄ d and
Effects of hydroxyurea in SCD: other mechanisms
escalated according to 2 weekly blood counts aiming for the
Finally, it has been suggested that hydroxyurea may
highest dose possible without myelosuppression (maximum
mediate some of its effects via nitric oxide. Studies in rats
tolerated dose; MTD). The results were impressive and
showed that metabolism of hydroxyurea leads to nitric
oxide release (Jiang et al, 1997). In humans, nitrosylhae-
• reduced annual rate of crises (2Æ5 in the treatment arm vs
moglobin can be detected in blood within 30 min of
4Æ5 in the placebo arm) P < 0Æ001
ingestion of hydroxyurea (Glover et al, 1999) and steady
• increased median time interval to first crisis (3Æ0 vs
state levels of nitric oxide metabolites can be detected
1Æ5 months) P ¼ 0Æ001
in hydroxyurea-treated subjects (Nahavandi et al, 2000,
Gladwin et al, 2002). This leads to the possibility that some
4Æ6 months) P < 0Æ001
of the clinical effects are mediated by nitric oxide-induced
• reduced incidence of acute chest syndrome (25 events vs
vasodilatation or reduced platelet activation.
51 events) P < 0Æ001
• reduced transfusion requirements (48 events vs 73
events) P ¼ 0Æ001
CLINICAL EFFICACY OF HYDROXYUREA
The MSH trial showed that hydroxyurea could ameliorate
IN ADULTS WITH SCD
the clinical course of SCD in some adults without serious
Initial reports of the use of hydroxyurea in SCD emerged in
short-term adverse effects and that the MTD was not always
the 1980s (Platt et al, 1984; Veith et al, 1985). These early
needed to achieve a clinical response. Although higher HbF
studies focused on the ability of hydroxyurea to increase
levels were associated with lower crisis rates, the association
HbF and improve laboratory parameters rather than clinical
was not statistically significant and neutrophil counts
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186
appeared to have the most impact, being associated with
hydroxyurea in children. A registry of European patients on
lower crisis rates throughout the whole study (Charache,
hydroxyurea has recently been established with the aim of
1997). In addition, the final HbF levels in the hydroxyurea
addressing these important questions (Davies & Roberts-
group did not differ markedly from their pretreatment levels
Harwood, 1998).
(5% vs 9%) (Steinberg et al, 1997a) and overall neither theinitial HbF nor the phenotype of the X-linked F-cell
Hydroxyurea and stroke in adults with SCD
production locus (FCP locus) predicted outcome, although
Hydroxyurea has many theoretical benefits in the treatment
the Central African Republic globin haplotype was associ-
and prevention of stroke. It lowers white cell count,
ated with a reduced response.
improves steady-state haemoglobin and reduces the risk of
Use of hydroxyurea was also shown to be cost effective,
acute chest syndrome: all risk factors for stroke (Ohene-
despite the rigorous monitoring used with 2 weekly clinic
Frempong et al, 1998). It also leads to improved rheological
visits and blood tests. Average annual costs were $16 810
properties of red cells and reduction in endothelial adhesion.
in the hydroxyurea group vs $22 020 in the placebo group
The only theoretical disadvantage is the increased whole
with the vast majority of cost being accounted for by
blood viscosity secondary to the rise in steady-state haemo-
inpatient admissions. This difference failed to reach statis-
globin. Despite these promising properties, the MSH study
tical significance. No account was taken of possible reduc-
did not show a statistical reduction in stroke although the
tions in long-term morbidity with treatment (Moore et al,
numbers involved (two in treatment group and three in
2000). Follow-up data after 6–7 years showed that there
placebo) were very small (Charache et al, 1995). It is
had been 51 deaths, 21 in the hydroxyurea group and 30 in
possible that hydroxyurea may have a role to play in
the placebo group (P ¼ 0Æ13); although because of the
patients coming off transfusion regimes, although prelim-
unblinding and subsequent switch of many patients to the
inary data in children suggest that this may be associated
treatment arm, these data are difficult to interpret. Analysis
with a significant risk of stroke recurrence (Ware et al,
according to hydroxyurea usage rather than original
1999). However, as most patients are unwilling or unable
treatment allocation suggests that the odds ratio for
to continue transfusions lifelong, many clinicians recom-
mortality during hydroxyurea use compared with no
mend stopping transfusions once patients reach adulthood
hydroxyurea use ranges from 0Æ59 (P ¼ 0Æ08) to 0Æ39
(Powars, 2000). Prospective randomized trials of hydroxy-
(P ¼ 0Æ001), depending upon assumptions made about
urea versus continuing transfusions will be required to
patients with incomplete data. There was no difference in
define the role of hydroxyurea in this setting.
the incidence of stroke in the hydroxyurea-treated patients.None of the patients have developed malignancies and,
HYDROXYUREA IN CHILDREN
although the incidence of acute chest syndrome wasreduced by hydroxyurea, pulmonary disease was the
The use of hydroxyurea in children potentially brings the
commonest cause of death (Steinberg et al, 1999).
greatest rewards in terms of prevention of end organdamage but also carries greater potential risks (Vichinsky,
Other trials of hydroxyurea in adults with SCD
1997). The possibility of adverse effects on growth and
A Cochrane review looking at the use of hydroxyurea in
development, and the risks of secondary malignancy in
SCD was published in February 2001 (Davies & Olujo-
groups exposed to the drug for long periods led to caution.
hungbe 2001). Twenty randomized or quasi-randomized
However, a number of promising phase I ⁄ II studies,
trials comparing hydroxyurea with placebo, standard
showing profound and sustained increases in HbF without
therapy or other interventions were found. Only two of
serious adverse events, led to larger scale trials (Scott et al,
these, the MSH study and the Belgian paediatric trial (see
1996; Kinney et al, 1999). The published studies of
below), were assessable. Problems with study design or data
hydroxyurea therapy in children with SCD are summarized
excluded the other 18. Despite these methodological
in Table II.
concerns, none of the published data conflict in anysubstantive way with the MSH findings. The vast majority
Evidence of efficacy
report increases in HbF, MCV and steady-state haemoglobin
Of the published studies, only four have focused on
along with clinical improvement in the number of painful
measures of clinical improvement in the severity of SCD
crises, hospital attendance rates and acute chest syndrome
(Ferster et al, 1996, 2001; Jayabose et al, 1996; Koren et al,
(el-Hazmi et al, 1992; Kutlar et al, 2000). Studies from the
1999) while the other studies have mainly assessed
developing world suggested hydroxyurea was no less
laboratory parameters of response and safety. The Belgian
effective in these populations (Lima et al, 1997; el-Alfy
paediatric trial of hydroxyurea in severe SCD first reported
in 1996 (Ferster et al, 1996), with the 5-year follow-up in
While these studies have been useful in establishing the
2001 (Ferster et al, 2001). The first study included 25
clinical effectiveness of hydroxyurea, they leave a number of
children (mean age 9 years) in a single-blind crossover
unanswered questions including: the optimum dose and
design with 6 months hydroxyurea (20–25 mg ⁄ kg ⁄ d) and
schedule, the potential for prospective identification of
6 months placebo. The follow-up study described 93
responders and non-responders to avoid exposure to a
patients (median age 7 years), including a small number
potentially toxic drug, the impact of treatment on long-term
of adults, who had a median follow-up of 3Æ5 years. There
organ damage, morbidity and mortality, and the safety of
was evidence in both studies of a reduction in hospital
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186
admissions and days spent in hospital, and evidence of a
reduced frequency of acute chest syndrome. Significant
increases in HbF and MCV with reduction in white cell and
reticulocyte counts were also seen. MTD was not needed for
efficacy and no important adverse events were noted.
Similar beneficial results with hydroxyurea have been
reported in the other clinical studies in children (Jayabose
et al, 1996; Koren et al, 1999).
In all the studies to date, growth and development appear
to be unaffected (Rogers, 1997; Wang et al, 2002) even in
children under school age (Hoppe et al, 2000) and in infants
(Wang et al, 2001). However, there is no evidence that
hydroxyurea prevents stroke or the recurrence of strokein children. The largest study included 16 children, three
of whom suffered a recurrent stroke within 16 weeksof changing from regular transfusions to hydroxyurea,although the dose and duration of hydroxyurea therapymay have contributed to these worrying results (Ware et al,1999).
Use of hydroxyurea in very young children
to prevent organ dysfunction
The development of end organ damage is closely associated
with morbidity and mortality in SCD (Platt et al, 1994). This
damage often starts early with evidence of splenic dysfunc-
tion by 6 months of age. This raises the possibility that
hydroxyurea might be able to exert a significant disease-
modifying effect if given to very young children with SCD.
An early report suggested that hydroxyurea use in two
young adults with sickle cell disease had led to reversal of
splenic dysfunction (Claster & Vichinsky, 1996). This wasnot confirmed by a trial in older children (12 ± 1Æ2 years)perhaps because splenic auto-infarction may well haveoccurred by this age (Olivieri & Vichinsky, 1998). However,in a 2-year pilot trial of hydroxyurea (20 mg ⁄ kg ⁄ d) in 28children aged 6–28 months (median 15 months) with HbSS
and Sbthalassaemia, Wang et al (2001) reported a lower
frequency of functional asplenia (47%) compared with the
expected frequency from historical data of 80% as assessed
by radionucleotide scanning. While this may indicate aclinical benefit of hydroxyurea in very young children withSCD, this study also showed that hydroxyurea is clearly notenough on its own to completely prevent the majorcomplications of the disease at this age. Two of the 28children in this study had neurological events, three had
acute chest syndrome and two had splenic sequestration
despite hydroxyurea treatment. These results emphasize
the still considerable
as to its role in
young children; a randomized controlled trial would seem
DOSE AND MONITORING OF HYDROXYUREA
The dose of hydroxyurea needed for maximal clinical
benefit appears not to be the same as the MTD. Although
with adverse clinical events in the form of invasive
infection or bleeding, it seems prudent to minimize doses
to reduce the risk of long-term toxicity, including secondary
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186
malignancies. Hydroxyurea is available as capsules of
occasional reports of aplasia lasting several weeks or
500 mg and syrup can be made up for paediatric use
months (Vichinsky & Lubin, 1994). As far as we are aware,
(generally 100 mg ⁄ ml) but is not widely available com-
there has never been a documented episode of life-
threatening infection associated with hydroxyurea-induced
The MSH study started patients at 10–15 mg ⁄ kg once
daily. Blood tests for full blood count, renal and liverfunction, along with HbF level were taken every 2 weeks.
Skin, gastrointestinal and renal
The dose was increased by 5 mg ⁄ kg ⁄ d every 12 weeks in
Cutaneous side-effects include nail hyperpigmentation,
the absence of bone marrow suppression (neutrophil
which is common, and increased skin pigmentation,
count < 2 · 109 ⁄ l, haemoglobin < 4Æ5 g ⁄ dl, reticulocytes
especially on the palms and soles (O'Branski et al, 2001).
or platelets < 80 · 109 ⁄ l). Once bone marrow suppression
Patients should be warned of this potential side-effect as it
had occurred, the dose was restarted at 2Æ5 mg ⁄ kg ⁄ d less
can be quite distressing. Hydroxyurea is associated with
than the toxic dose and this was defined as the MTD. Most
development of leg ulcers in myeloproliferative diseases and
patients achieved a dose of 20–25 mg ⁄ kg ⁄ d although some
some studies have quoted rates of up to 30% in SCD patients
tolerated 35 mg ⁄ kg ⁄ d. Some patients, however, showed
on hydroxyurea, but the role of hydroxyurea is unclear as
toxicity at levels of only 2Æ5 mg ⁄ kg ⁄ d.
90% of these patients had a prior history of ulcers (Chaine
Most studies in children have used doses of approximately
et al, 2001). In the MSH study, 32% of patients had leg
20 mg ⁄ kg ⁄ d. Unfortunately, there have been few studies
ulcers at enrolment and new ulcers developed with equal
looking at alternative dosing regimes. In general, our
frequency in treatment and placebo groups (Charache et al,
practice is to start at a dose of 15–20 mg ⁄ kg ⁄ d. Full blood
1995). Nausea, rash and other gastrointestinal upsets have
count (FBC), including reticulocytes, HbF level, renal and
been described with hydroxyurea (de Montalembert et al,
liver function tests, are performed prior to commencing
1999) but, in randomized trials, are no commoner than
treatment. FBC and reticulocytes should be repeated at
with placebo (Charache et al, 1995). Hydroxyurea is renally
2 weeks and then at 2–4 week intervals during the initial
excreted and small increases in creatinine are sometimes
phases of treatment. Renal and liver function should be
seen on treatment. Renal function should be monitored;
checked at least monthly. Once the patient is well estab-
dose reductions are needed in patients with renal failure.
lished on a stable dose, monthly blood counts should suffice.The interval between counts should never exceed 6 weeks.
Pregnancy and teratogenicity
Caution should be taken in issuing repeat prescriptions
Studies in rats showed an increase in post-implantation
without a recent blood count and supply should probably
losses, and reduced fetal and placental weights (Spencer
not exceed 4–6 weeks worth at any one time. Patients are
et al, 2000). Despite strict instructions to take contraceptive
asked to report any fever, sore mouth or other worrying
precautions for both men and women patients on treat-
symptoms and have a blood count done in these circum-
ment, there have been a number of pregnancies in
stances. When monitoring the response to hydroxyurea, the
published studies. More than 14 cases have now been
effect on clinical well-being is probably more important than
described: three pregnancies were terminated electively, one
any absolute increase in HbF levels. Patients that fail to
infant was stillborn in a mother with eclampsia and the
respond clinically to 20 mg ⁄ kg ⁄ d can have their dose
other 10 resulted in healthy live-born infants with no
escalated as long as there is no evidence of marrow
congenital abnormalities (Byrd et al, 1999). Patients on
hydroxyurea should be advised as to the theoretical risks of
Although most cases of poor response are due to com-
pregnancy and those wishing to conceive should stop
pliance (Steinberg et al, 1997a), there appear to be some
treatment 3–6 months before switching to unprotected
individuals who are biologically resistant to hydroxyurea
(Yang et al, 1997). Addition of erythropoietin has helpedin a small number of cases (el-Hazmi et al, 1995). Because
of concerns about long-term toxicity, it is probably wise to
The Polycythemia Study Group showed a trend towards
withdraw treatment in any patient who has had no
increased second malignancies after 8 years in a small study
of 51 patients treated with hydroxyurea (9Æ8% vs 3Æ7% in
3–6 months of treatment. It is worth noting that labor-
historical control group; P ¼ 0Æ1) (Fruchtman et al, 1997).
atory methods for measurement of HbF have generally
A larger study of 150 patients with polycythaemia rubra
been developed to measure fairly low levels. It is import-
vera diagnosed before the age of 65 showed an actuarial
ant to ensure that the method used is reliable at higher
risk of leukaemia of about 10% by the 13th year of
HbF concentrations (Epstein et al, 1996; Schultz, 1999).
treatment and a 15% rate of other cancers, although thiswas only slightly greater than the expected rate of 11Æ5% inpatients of this age group (Najean & Rain, 1997). A more
LONG-TERM TOXICITY AND SAFETY
suitable comparison group might be young patients with
erythrocytosis secondary to inoperable congenital heart
disease; a study of 64 patients treated with hydroxyurea for
The commonest side-effect is dose-dependent myelosuppres-
2–15 years showed no increase in malignancy (Triadou
sion. Although this is usually transient, there have been
et al, 1994). Initial pilot studies of hydroxyurea showed that
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186
Table III. Patients with SCD who have developed malignancies while on treatment withhydroxyurea.
hydroxyurea treatment
Ferster et al (2001)
Raunch et al (1999)
Hodgkin's lymphoma
Moschovi et al (2001)
AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome.
some adults had pre-existing chromosomal breaks in
similar advantages of treatment in other sickling conditions
peripheral blood leucocytes but there was no progression
especially sickle b-thalassaemia (Voskaridou et al, 1995;
through treatment and no difference from HbSS and HbAA
Loukopoulos et al, 2000; Rigano et al, 2001). Theoretically
controls (Charache et al, 1987). More worrying are experi-
hydroxyurea may be even more effective in this group of
mental studies of acquired DNA mutations in children
disorders than in HbSS as HbF production has the added
treated for between 7 and 30 months that showed an
advantage of mopping up excess a-chains responsible for
increased mutation rate as measured by the VDJ recombi-
some of the ineffective erythropoiesis. Results in HbSC
nation assay. Although this was significantly greater than
disease are more difficult to interpret. An initial study of six
with control children (P ¼ 0Æ04), it was still within the
patients showed an increase in haemoglobin levels and
normal range for age (Hanft et al, 2000).
MCV, and a decrease in reticulocytes and bilirubin on
There have now been four reported cases of malignancy
treatment but no statistically significant change in HbF
in sickle cell patients on hydroxyurea (Table III). Patients 1
levels (Steinberg et al, 1997b). A more recent trial in six
and 4 are likely to be unrelated to treatment, given the time
children with HbSC showed a significant rise in HbF and a
course and type of malignancy. Cases 2 and 3 are more
good clinical response with a marked reduction in hospital
doubtful. It is difficult to judge risk as the denominator in
admission rates (Miller et al, 2001). It is unlikely that these
terms of total number of sickle cell patients on hydroxyurea
patients are intrinsically resistant to hydroxyurea and
is unknown. The earliest large-scale recruitment to trials
therefore there seems no reason to deny severely affected
began in 1992 so we have now accumulated 10 years
individuals a trial of therapy. Case reports documenting
worth of experience. The risk appears small but continued
beneficial effects of hydroxyurea in HbSD-Punjab and HbSO-
caution is needed (Ho & Murgo, 1995; Silver, 1995;
Arab disease can also be found (Rogers, 1997; Udden et al,
de Montalembert & Davies 2001).
HYDROXYUREA FOR SICKLING DISORDERS
Based on the evidence reviewed above, hydroxyurea plays
Initial studies were confined to patients with homozygous
an important role in the management of a number of
sickle cell disease. Smaller scale studies have confirmed
complications of SCD. This is summarized in Table IV.
Table IV. The role of hydroxyurea in SCD.
Evidence for hydroxyurea
Treatment of choice in severely affected adult patients (‡3 hospital admissions per year).
vaso-occlusive crises
Probably similar efficacy in children but concerns surrounding long-term toxicity so reserve for patientswith severe disease despite intensive supportive care.
Proven reduction in acute chest syndrome in adults and supportive evidence in children.
Should be the treatment of choice in all patients with ‡ 2 episodes in preceding 1–2 years.
No evidence that hydroxyurea can reduce the incidence of first or recurrent strokes.May have a role in patients coming off transfusion programmes.Need controlled clinical trials to establish role.
No evidence for prevention or treatment of leg ulcers, priapism, osteonecrosis, splenic or hepatic sequestration.Need to test in controlled clinical trials.Insufficient data to comment on prevention of organ dysfunction, needs larger trials with prolonged follow-up.
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186
Recurrent vaso-occlusive crises
Benkerrou, M., Delarche, C., Brahimi, L., Fay, M., Vilmer, E., Elion,
For the majority of adults with SCD, hydroxyurea can be
J., Gougerot-Pocidalo, M.-A. & Elbim, C. (2002) Hydroxyurea
recommended as the treatment of choice for preventing
corrects the dysregulated L-selectin expression and increased
vaso-occlusive crises in patients who have frequent, debi-
H2O2 production of polymorphonuclear neutrophils frompatients with sickle cell anemia. Blood, 99, 2297–2303.
litating vaso-occlusive crises especially where these lead to
Bridges, K.R., Barabino, G.D., Brugnara, C., Cho, M.R., Christoph,
‡ 3 hospital admissions per year or to excessive time lost
G.W., Dover, G., Ewenstein, B.M., Golan, D.E., Guttmann, C.R.,
from work or higher education. Close monitoring for
Hofrichter, J., Mulkern, R.V., Zhang, B. & Eaton, W.A. (1996) A
toxicity is essential and this, or worries about possible
multiparameter analysis of sickle erythrocytes in patients
long-term toxicity, may lead many patients to decline this
undergoing hydroxyurea therapy. Blood, 88, 4701–4710.
option. Unfortunately, there are as yet no other pharmaco-
Byrd, D.C., Pitts, S.R. & Alexander, C.K. (1999) Hydroxyurea in two
logical agents available with equivalent efficacy and the
pregnant women with sickle cell anemia. Pharmacotherapy, 19,
risks associated with chronic transfusion make this an
unattractive approach for vaso-occlusive crises. For children
Chaine, B., Neonato, M.G., Girot, R. & Aractingi, S. (2001) Cuta-
with recurrent painful crises, every attempt should be made
neous adverse reactions to hydroxyurea in patients with sicklecell disease. Archives of Dermatology, 137, 467–470.
to educate and support the family about the best ways to
Charache, S. (1997) Mechanism of action of hydroxyurea in the
prevent and cope with recurrent crises, as this will often be
management of sickle cell anemia in adults. Seminars in Hema-
sufficient to reduce the frequency of hospital admissions.
tology, 34, 15–21.
Psychologists with special expertise in SCD are often very
Charache, S., Dover, G.J., Moyer, M.A. & Moore, J.W. (1987)
valuable in more severe cases. Hydroxyurea should be
Hydroxyurea-induced augmentation of fetal hemoglobin pro-
reserved for children who have ongoing problems even after
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2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 177–186

Acorda Data on Inhaled Levodopa Therapy CVT-301 Recognized in Blue Ribbon Highlights Session at International Congress of Parkinson's Disease and Movement Disorders ARDSLEY, N.Y.--(BUSINESS WIRE)-- Acorda Therapeutics, Inc. (Nasdaq:ACOR) today announced that data from aPhase 2b clinical trial of CVT-301, an inhaled levodopa (L-dopa) under development for the episodic treatment ofOFF episodes associated with Parkinson's disease (PD), was included in the Blue Ribbon Highlights Session of the19th International Congress of Parkinson's Disease and Movement Disorders (MDS). Selected by a panel of experts,the Blue Ribbon Highlights Session provided a critical review of the best poster presentations, highlightingrelevance, novelty and quality of both clinical data and basic research. "Inhaled Levodopa (CVT-301) Provides RapidImprovement of OFF States in Parkinson's Disease" was one of only 19 posters selected from among the almost1,500 poster presentations at this year's conference.